WO2010135493A2 - Agents d'imagerie utilisés pour la maladie d'alzheimer - Google Patents

Agents d'imagerie utilisés pour la maladie d'alzheimer Download PDF

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WO2010135493A2
WO2010135493A2 PCT/US2010/035517 US2010035517W WO2010135493A2 WO 2010135493 A2 WO2010135493 A2 WO 2010135493A2 US 2010035517 W US2010035517 W US 2010035517W WO 2010135493 A2 WO2010135493 A2 WO 2010135493A2
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compound
compounds
independently
alkyl
amyloid
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WO2010135493A3 (fr
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Mark M. Goodman
Fanxing Zeng
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Emory University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • AD Alzheimer's disease
  • a ⁇ amyloid- ⁇
  • NFTs neurofibrillary tangles
  • amyloid plaques The major component of amyloid plaques is a small 39-43 amino acid long ⁇ -amyloid peptide that is generated from the cleavage of a larger amyloid precursor protein.
  • amyloid plaques are complex lesions containing numerous associated cellular products. Mutations causing increased production of the 42-43 amino acid form of this peptide have been genetically linked to autosomal dominant familial forms of Alzheimer's disease. Deposits of ⁇ -amyloid peptide occur very early in the disease process, long before clinical symptoms develop. Although the exact mechanisms underlying AD are not fully understood, ⁇ -amyloids are widely believed to play a causal role in the disease.
  • amyloid deposits are causal, they are certainly a key part of the diagnosis. Because amyloid plaques occur early in the disease, the ability to image amyloid plaques would provide a convenient means for early diagnosis and prevention of the disease as well as a method for monitoring effectiveness of therapeutic agents for the disease.
  • Amyloid deposits are shown to be present in diseases such as Mediterranean fever, Muckle-Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstamnn-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid, ⁇ 2 -microglobulin amyloid in dialysis patients, inclusion body myositis, ⁇ 2 -amyloid deposits in muscle wasting disease, and Islets of Langerhans diabetes Type Il insulinoma.
  • diseases such as Mediterranean fever, Muckle-Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, am
  • ligands useful for detecting amyloid plaque aggregates in the living brain must cross the intact blood- brain barrier.
  • ligands that are relatively small in size and lipophilic have been sought as candidate imaging agents for amyloid plaques.
  • Patent 6,001 ,331 discloses a method of imaging amyloid deposits using radiolabeled benzothiazole derivatives
  • WO 2004/032975 describes various biphenyls and fluorenes as imaging agents in Alzheimer's disease
  • WO 2004/064869 discloses metal-chelating agents for the diagnosis, prevention, and treatment of pathophysiological conditions associated with amyloid accumulation
  • US 2005/0043377 describes further thioflavin derivatives for in vivo imaging and prevention of amyloid deposition.
  • WO 2006/035316 describes derivatives for imaging amyloid deposits.
  • Alzheimer's disease affects approximately 20 to 40% of the population over 80 years of age, the fastest growing age group in the United States and other post-industrial countries, there is a continuing need for an agent with high selectivity and specificity for binding amyloid deposits or plaques which can be used in a simple, noninvasive method for in vivo imaging and quantitating amyloid deposits in a patient. Such an agent will allow early detection and monitoring of treatment efficacy for maximum cognitive preservation.
  • the present invention provides compounds and compositions which bind to amyloid ⁇ plaques.
  • the compounds and compositions of the invention can be readily labeled with positron emitting radio-elements such as carbon-11 and fluohne-18 or single photon radio-elements.
  • the compounds and compositions of the invention are useful for identifying amyloid ⁇ plaques via PET or SPECT imaging, for example.
  • the compounds and compositions of the invention are useful for detecting and quantitating amyloid deposits.
  • the compounds and compositions are also useful in inhibiting the aggregation of amyloid proteins to form amyloid deposits and in delivering a therapeutic agent selectively and specifically to amyloid deposits.
  • Z is O, S, N or NH;
  • R2 and R3 are each independently H, Ci-4 aminoalkyl, C1-4 haloalkyl or C1-C4 alkyl;
  • each n is independently an integer from 0 to 7;
  • each X is independently I, F, Br or Cl;
  • R4 and Rs are each independently selected from the group consisting of: H, X, OH,
  • both E and G are CH.
  • one of E and G is N and the other of E and G is CH.
  • Z is S.
  • Z is NH.
  • B and D are CH.
  • B and D are CH and A is C-Y.
  • R4 and R5 are H.
  • one of R5 or R6 is halogen, -OMe, or -OH and the other of R5 or R6 is H.
  • the compounds of formula I there are four nitrogen atoms as ring substituents. In an embodiment of the compounds of formula I, there is one halogen atom present as a substituent. In an embodiment of the compounds of formula I, the compound is radiolabeled. In an embodiment, provided is a compound of formula I wherein B and D are C-Y and Y is H.
  • R 2 and R 3 are each independently H, Ci -4 aminoalkyl, Ci -4 haloalkyl or CrC 4 alkyl;
  • one of R2 and R3 is hydrogen and the other of R2 and R3 is C1 -C4 alkyl.
  • Z is S, N or NH;
  • R2 and R3 are each independently H, Ci-4 aminoalkyl, C1-4 haloalkyl or C1-C4 alkyl;
  • each n is independently an integer from O to 7;
  • each X is independently I, F, Br or Cl;
  • R4 and Rs are each independently selected from the group consisting of: H, X, OH
  • J is N. In an aspect of compounds of formula III, J is CH. In an aspect of compounds of formula III, one or J, A, B, and D is N and the others of J, A, B and D are CH or C-Y. In an aspect of compounds of formula III, Z is NH. In an aspect of compounds of formula III, J, A or D is C-Y and Y is a halogen.
  • Z is S, N or NH;
  • R2 and R3 are each independently H, Ci-4 aminoalkyl, C1-4 haloalkyl or C1-C4 alkyl;
  • J is N. In an aspect of compounds of formula IV, J is CH. In an aspect of compounds of formula IV, one or J, A, B, and D is N and the others of J, A, B and D are CH or C-Y. In an aspect of compounds of formula IV, Z is NH. In an aspect of compounds of formula IV, J, A or D is C-Y and Y is a halogen.
  • X is selected from the group consisting of: I, F, Br and Cl.
  • R4 and R5 are each independently selected from the group consisting of: H; X; OH; C1 -C4 alkyl; and O-(C1 -C4 alkyl).
  • X is 124 I, 125 I, 131 I, 123 1, 76 Br, 77 Br, 82 Br, 18 F, or 32 CI.
  • radiolabeled compound of any of the formulas described herein is provided.
  • “radiolabeled” means a compound in which the naturally occurring isotope of an element is replaced with a radioisotope of the element (also referred to as “isotopically labeled”).
  • a compound of the invention may have more than one radiolabel.
  • any of F, Cl, Br, I, O or C in the formulas shown herein may be in stable isotopic or radioisotopic form.
  • Particularly useful radioisotopic labels are 18 F, 123 I, 125 I, 131 1, 76 Br, 77 Br, 18 O and 11 C.
  • one or more F, Br or I in the formulas provided herein is in radioisotopic form.
  • any F, Br or I in the formulas provided herein is in radioisotopic form.
  • R 2 and R 3 are each independently H, C1 -4 aminoalkyl, C1 -4 haloalkyl or C1 - C4 alkyl;
  • X is I, F, Br or Cl;
  • a pharmaceutical composition comprising a compound of Formula I-V and a pharmaceutically acceptable carrier.
  • diagnostic composition for imaging amyloid deposits comprising a radiolabeled compound of formula I-V.
  • a method of inhibiting amyloid plaque aggregation in a mammal comprising administering the composition of Formula I-V in an amount effective to inhibit amyloid plaque aggregation.
  • a method of imaging amyloid deposits comprising: a) introducing into a mammal a detectable quantity of a diagnostic composition of Formula I -V; b) allowing sufficient time for the labeled compound to become associated with amyloid deposits; and c) detecting the labeled compound associated with one or more amyloid deposits.
  • the detection is performed using PET or SPECT imaging.
  • compositions of the invention bind to amyloid deposits with high affinity and selectivity.
  • inventive compounds labeled with an appropriate radioisotope are useful as imaging agents for visualizing the location and density of amyloid deposits by PET and SPECT imaging, for example. Accordingly, the labeled compounds of the invention are useful for diagnostic imaging and evaluating efficacy of any therapeutic compounds for Alzheimer's disease.
  • a method of imaging amyloid deposits comprises (a) introducing into a subject a detectable quantity of a labeled compound of Formula I-V; and/or a pharmaceutically acceptable salt, ester or amide thereof; (b) allowing sufficient time for the labeled compound to become associated with amyloid deposits; and (c) detecting the labeled compound associated with one or more amyloid deposits.
  • the present invention also provides diagnostic compositions comprising a radiolabeled compound of Formula I-V and/or a pharmaceutically acceptable carrier or diluent. Also within the scope of the invention are pharmaceutical compositions which comprise a compound of Formula I-V and/or a pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions are useful for inhibiting the aggregation of amyloid proteins or for delivering a therapeutic agent to a subject. Also provided are pharmaceutically acceptable salts of the compounds of Formula I -V. Also provided herein are methods of making the compounds of Formula I-V. Methods of quantitating amyloid deposits are also provided herein. BRIEF DESCRIPTION OF THE FIGURES
  • Figure 1 shows the time-activity curves of brain regions for [ 18 F]-FZ 2-
  • Figure 2 shows the portions of the brain used for Figure 1.
  • pharmaceutically acceptable salt refers to those carboxylate salts or acid addition salts of the compounds of the present invention which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts derived from nontoxic organic acids such as aliphatic mono and dicarboxylic acids, for example acetic acid, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids.
  • aliphatic mono and dicarboxylic acids for example acetic acid, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids.
  • Further representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, propionate, pivalate, cyclamate, isethionate, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, Berge S. M, et al., Pharmaceutical Salts, J. Pharm. Sci. 66:1 -19 (1977) which is incorporated herein by reference.
  • the term, "pharmaceutically acceptable carrier,” as used herein, is an organic or inorganic composition which serves as a carrier/stabilizer/diluent of the active ingredient of the present invention in a pharmaceutical or diagnostic composition.
  • the pharmaceutically acceptable carriers are salts.
  • Further examples of pharmaceutically acceptable carriers include but are not limited to water, phosphate-buffered saline, saline, pH controlling agents (e.g. acids, bases, buffers), stabilizers such as ascorbic acid, isotonizing agents (e.g. sodium chloride), aqueous solvents, a detergent (ionic and non-ionic) such as polysorbate or TWEEN 80.
  • alkyl refers to both straight and branched chain radicals of up to 8 carbons, preferably 6 carbons, more preferably 4 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t- butyl, and isobutyl.
  • alkoxy is used herein to mean a straight or branched chain alkyl radical, as defined above, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • the alkoxy chain is 1 to 6 carbon atoms in length, more preferably 1 -4 carbon atoms in length.
  • alkylamine or "aminoalkyl” as used herein by itself or as part of another group refers to an amino group which is substituted with one or more alkyl groups as defined above.
  • haloalkyl means an alkyl group substituted with one or more halo groups.
  • dialkylamine or other forms of the phrase as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups as defined above.
  • halo employed herein by itself or as part of another group refers to a halogen atom, including chlorine, bromine, fluorine or iodine.
  • aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
  • heterocycle or "heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7- membered mono-heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatom may optionally be oxidized.
  • rings contain one nitrogen combined with one oxygen or sulfur, or two nitrogen heteroatoms.
  • heterocyclic groups include piperidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazlinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, homopiperidinyl, homopiperazinyl, pyridazinyl, pyrazolyl, and pyrazolidinyl, most preferably thiamorpholinyl, piperazinyl, and morpholinyl.
  • heteroatom is used herein to mean an oxygen atom ("O"), a sulfur atom (“S”) or a nitrogen atom (“N”). It will be recognized that when the heteroatom is nitrogen, it may form an NR a R b moiety, wherein R a and R b are, independently from one another, hydrogen or Ci -4 alkyl, C 2-4 aminoalkyl, Ci -4 halo alkyl, halo benzyl, or R 1 and R 2 are taken together to form a 5- to 7-member heterocyclic ring optionally having O, S or NR C in said ring, where R c is hydrogen or Ci -4 alkyl.
  • heteromatic is used herein to mean an aromatic ring substituted with one or more heteroatoms and may contain substituents including halogens, alkyl, alkoxy, alkythio, alkenyl, allynyl, haloalkyl, haloalkoxy, haloalkythio, haloalkenyl, haloalkynyl, haloaromatic and haloheteroaromatic.
  • the present invention also includes isomers, including stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers which arise as a consequence of structural asymmetry.
  • Each individual stereoisomer and optical isomer is intended to be included separately and is intended to be able to be included and excluded in the claims if necessary or desirable. It is understood that there are methods known in the art to synthesize separate isomers or separate isomers from a mixture.
  • the compounds of the invention may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • Exemplary compounds of the invention have been evaluated for their binding affinities via the binding competition with known compound PIB using human AD cortical tissues.
  • Ki inhibition constants
  • Table 1 and 2 The inhibition constants Ki (nM), for the competitive inhibition of the unlabeled compounds for amyloid- ⁇ plaques and neurofibrillary tangles vs.[ 3 H]PIB using postmortem AD homogenate tissues is shown in Table 1 and 2.
  • Table 1 and 2 show that certain compounds of the invention have higher affinity for amyloid plaques than PIB or IMPY.
  • the rank in affinity of the compounds tested was FZ 2-107 > FZ 2-111 > FZ 2-110 > FZ 2-100 > PIB >IMPY >FZ 2-114 > FZ 2-112.
  • IC50 values for certain compounds The different data obtained for the same compounds represent differences in experimental conditions and other factors.
  • Tables 1 and 2 are derived from human amyloid from post mortem AD subjects whereas Table 3 is from synthetic AD homogenate tissue. Procedure:
  • Binding assays were carried out in 12 x 75 mm borosilicate glass tubes. All compounds were prepared as 1 mM dimethyl sulfoxide (DMSO) stocks solution before dilution into PBS. The maximum final concentration of DMSO in the assays was 0.25%.
  • the reaction mixture contained 50 ml. of A ⁇ (1-40) aggregates (0.86 mg in the final assay mixture), 100 mL of [ 3 H]BTA-I (0.8-1 nM diluted in PBS) and 500 mL of inhibitors (3.10 "6 to 10 "11 M diluted serially in PBS containing 0.5% DMSO) in a final volume of 1 mL.
  • Non specific binding was defined in the presence of 3 mM of PIB in the same assay tubes.
  • the mixture was incubated at room temperature for 120 min, and the bound and free fractions were separated by vacuum filtration through Whatman GF/B glass filters using a Brandel M- 24 cell harvester followed by 2 x 2 mL washes with PBS. Filters containing the bound ligand were counted in a gamma counter. Values for the half-maximum inhibitory concentration (IC 50 ) were determined from displacement curves of three independent experiments in triplicate subject to non linear regression analysis using GraphPad Prism.
  • K 1 IC 50 /(1 +[L]/K d ), where [L] is the concentration of [3H]BTA-I used in the assay, and K d is the dissociation constant of BTA-1.
  • the compounds disclosed are excellent imaging agents for amyloid plaques.
  • the inventive compounds can readily penetrate the intact blood-brain barrier and be retained in the brain sufficiently long enough for imaging. These compounds exhibit specific brain uptake over other tissues in vivo.
  • the skilled artisan can evaluate a compound of the invention as an imaging agent for amyloid plaques by various art-known methods and assays as disclosed herein. For example, a given compound can be tested for binding specificity and selectivity for amyloid deposits in an in vitro competitive binding assay using suitable cells, tissues or beta amyloid peptides, along with a known imaging agent as a control, as described in the present application.
  • the compound shows desired binding characteristics for amyloid plaques, it can then be further evaluated in vivo, i.e., for brain uptake, selective and specific binding for amyloid deposits, by measuring distribution in various tissues after administration into an animal (e.g. rhesus monkey).
  • kits can contain a final product labeled with an appropriate isotope ready to use for imaging or a penultimate product (e.g. compounds of formula I-V having Sn(alkyl) 3 at the X position) and a label (e.g. K[ 18 F]F) with reagents such that a final product can be made at the site or time of use.
  • a penultimate product e.g. compounds of formula I-V having Sn(alkyl) 3 at the X position
  • a label e.g. K[ 18 F]F
  • compounds of the invention are useful in imaging.
  • the compounds are useful for in vivo imaging.
  • the compounds are useful for in vitro imaging.
  • a radiolabled compound of Formula I-V is introduced into a tissue or a patient in a detectable quantity.
  • the compound is typically part of a pharmaceutical composition and is administered to the tissue or the patient by methods well known to those skilled in the art.
  • the compound can be administered either orally, rectally, parenterally (intravenous, by intramuscularly or subcutaneously), intracistemally, intravaginally, intraperitoneal ⁇ , intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.
  • parenterally intravenous, by intramuscularly or subcutaneously
  • intracistemally intravaginally
  • intraperitoneal ⁇ intravesically
  • the labeled compound is detected noninvasively inside the patient.
  • a labeled compound of the invention is introduced into a patient, sufficient time is allowed for the compound to become associated with amyloid deposits, and then a sample of tissue from the patient is removed and the labeled compound in the tissue is detected apart from the patient.
  • a tissue sample is removed from a patient and a labeled compound of the invention is introduced into the tissue sample. After a sufficient amount of time for the compound to become bound to amyloid deposits, the compound is detected.
  • tissue means a part of a patient's body. Examples of tissues include the brain, heart, liver, blood vessels, and arteries.
  • a detectable quantity is a quantity of labeled compound necessary to be detected by the detection method chosen.
  • a labeled compound to be introduced into a patient in order to provide for detection can readily be determined by those skilled in the art. For example, increasing amounts of the labeled compound can be given to a patient until the compound is detected by the detection method of choice.
  • a label is introduced into the compounds to provide for detection of the compounds.
  • a "patient" is any organism to which a compound of the invention is desired to be administrated. In embodiments, a patient is a mammal. In embodiments, a patient is a human.
  • the administration of the labeled compound to a patient can be by a general or local administration route.
  • the labeled compound may be administered to the patient such that it is delivered throughout the body.
  • the labeled compound can be administered to a specific organ or tissue of interest. For example, it is desirable to locate and quantitate amyloid deposits in the brain in order to diagnose or monitor the progress of Alzheimer's disease in a patient.
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the label that is introduced into the compound will depend on the detection method desired. For example, if PET is selected as a detection method, the compound must possess a positron-emitting atom, such as 11 C or 18F.
  • Fluorine-18 is currently the most desirable positron emitting radioelement because its 110 minute half life allows sufficient time for radiosynthesis, purification of the final product and transportation to hospitals or other sites from the cyclotron or radiopharmacy. Also, fluorine-18 can be prepared in curie quantities as fluoride ion which can be used for automated radiosynthetic procedures (see Applied Radiation and Isotopes 58:657 (2003)). Radiopharmaceuticals of very high specific activity can be obtained in a theoretical, 1.7 Ci/nmol specific activity that can be calculated for a no-carrier-added fluorine-18 fluoride ion nucleophilic substitution reaction. Fluorine-18 is the lowest energy positron emitter (0.635 MeV, 2.4 mm positron range) which affords the highest spatial resolution in PET images. Other radioisotope labels are also useful.
  • the cyclic and non-cyclic compounds of the invention can be labeled with Technetium to produce Tc-complexed compounds.
  • Technetium-99m is known to be useful radionuclides for SPECT imaging.
  • the compounds of the invention are joined to a Tc-99m metal cluster through a 4-6 carbon chain which can be saturated or possess a double or triple bond.
  • the Tc-99m metal cluster can be, for example, an alkylthiolato complex, a cytectrene or a hydrazino nicotinamide complex (HYNIC), a cyclopentadienetricarbonyl or an N287 chelate.
  • HYNIC hydrazino nicotinamide complex
  • the linking structure can be R 5 where R 5 is Z-(CH 2 ) a -CH b -CH, where a is 1 , 2 or 3, b is 0, 1 or 2, and Z is an alkylthiolato-Tc complex, a Tc-cytectrene or a Tc-HYNIC complex or other Tc chelate as known in the art.
  • R 5 is Z-(CH 2 ) a -CH b -CH, where a is 1 , 2 or 3, b is 0, 1 or 2, and Z is an alkylthiolato-Tc complex, a Tc-cytectrene or a Tc-HYNIC complex or other Tc chelate as known in the art.
  • the synthesis and use of Tc-99m complexes of compounds of the invention are known in the art.
  • the radioactive diagnostic agent should have sufficient radioactivity and radioactivity concentration which can assure reliable diagnosis.
  • the radioactive metal being technetium-99m (“Tc-99m complexed compounds”)
  • it may be included usually in an amount of 0.1 to 50 mCi in about 0.5 to 5.0 ml at the time of administration.
  • the amount of a compound of Formula I-V may be such as sufficient to form a stable chelate compound with the radioactive metal.
  • the inventive compound as a radioactive diagnostic agent is sufficiently stable, and therefore it may be immediately administered as such or stored until its use.
  • the radioactive diagnostic agent may contain any additive such as pH controlling agents (e.g., acids, bases, buffers), stabilizers (e.g., ascorbic acid) or isotonizing agents (e.g., sodium chloride).
  • pH controlling agents e.g., acids, bases, buffers
  • stabilizers e.g., ascorbic acid
  • isotonizing agents e.g., sodium chloride
  • inventive compounds are particularly useful for imaging amyloid deposits in vivo.
  • One of the key prerequisites for an in vivo imaging agent of the brain is the ability to cross the intact blood-brain barrier after a bolus intravenous injection.
  • the compounds disclosed herein possess a core ring system comprised of various substituted, fused 5- and 6-member aromatic rings.
  • Several compounds of this invention contain a thiazolopyridine core. These compounds contain no quaternary ammonium ion, therefore, they are relatively small in size, neutral and lipophilic.
  • Another aspect of the invention is a method of inhibiting amyloid plaque aggregation.
  • the present invention also provides a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, by administering to a patient an amyloid inhibiting amount of a compound of the invention.
  • an amyloid inhibiting amount by simply administering a compound of the invention to a patient in increasing amounts until the growth of amyloid deposits is decreased or stopped.
  • the rate of growth can be assessed using imaging as described above or by taking a tissue sample from a patient and observing the amyloid deposits therein.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1 ,000 mg per day.
  • a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient.
  • the specific dosage used can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
  • isotopic variants of compounds disclosed herein are intended to be encompassed by the disclosure.
  • any one or more hydrogens in a molecule disclosed can be replaced with deuterium or tritium.
  • Isotopic variants of a molecule are generally useful as standards in assays for the molecule and in chemical and biological research related to the molecule or its use. Specific names of compounds are intended to be exemplary, as it is known that one of ordinary skill in the art can name the same compounds differently.
  • ionizable groups groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)]. All possible ionic forms of such molecules and salts thereof are intended to be included individually in the disclosure herein. With regard to salts of the compounds herein, one of ordinary skill in the art can select from among a wide variety of available countehons those that are appropriate for preparation of salts of this invention for a given application.
  • an administered dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration.
  • the severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods.
  • the dose and perhaps dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above also may be used in veterinary medicine.
  • Such agents may be formulated and administered systemically or locally.
  • Techniques for formulation and administration may be found in Alfonso and Gennaro (1995). Suitable routes may include, for example, oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, or intramedullary injections, as well as intrathecal, intravenous, or intraperitoneal injections.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the compositions of the present invention, in particular those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • Appropriate compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Agents intended to be administered intracellular ⁇ may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes, then administered as described above. Liposomes are spherical lipid bilayers with aqueous interiors. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external microenvironment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. Additionally, due to their hydrophobicity, small organic molecules may be directly administered intracellular ⁇ .
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions, including those formulated for delayed release or only to be released when the pharmaceutical reaches the small or large intestine.
  • the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.

Abstract

Cette invention concerne des composés et des méthodes d'imagerie de dépôts amyloïdes utilisant des composés marqués par radioactivité. Cette invention concerne également une méthode d'inhibition de l'agrégation de protéines amyloïdes formant des plaques ou dépôts amyloïdes, une méthode de détermination de la capacité d'un composé thérapeutique à inhiber l'agrégation des protéines amyloïdes, et une méthode permettant d'administrer un agent thérapeutique à ces dépôts amyloïdes.
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CN107501123A (zh) * 2017-07-03 2017-12-22 华中科技大学鄂州工业技术研究院 带永久电荷肼类糖标记物的制备方法及应用

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CN107501123B (zh) * 2017-07-03 2020-04-28 华中科技大学鄂州工业技术研究院 带永久电荷肼类糖标记物的制备方法及应用

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